Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention.

Early developmental conditioning of later health and disease: physiology or pathophysiology?

The environment in which the fetus develops is critical for its survival and long-term health. The regulation of normal human fetal growth involves many multidirectional interactions between the mother, placenta, and fetus. The mother supplies nutrients and oxygen to the fetus via the placenta. The fetus influences the provision of maternal nutrients via the placental production of hormones that regulate maternal metabolism. The placenta is the site of exchange between mother and fetus and regulates fetal growth via the production and metabolism of growth-regulating hormones such as IGFs and glucocorticoids. Adequate trophoblast invasion in early pregnancy and increased uteroplacental blood flow ensure sufficient growth of the uterus, placenta, and fetus. The placenta may respond to fetal endocrine signals to increase transport of maternal nutrients by growth of the placenta, by activation of transport systems, and by production of placental hormones to influence maternal physiology and even behavior. There are consequences of poor fetal growth both in the short term and long term, in the form of increased mortality and morbidity. Endocrine regulation of fetal growth involves interactions between the mother, placenta, and fetus, and these effects may program long-term physiology.

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Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus.

https://www.cell.com/developmental-cell/pdf/S1534-5807(04)00468-X.pdf

The placenta is a niche for hematopoietic stem cells.

The placenta is essential for sustaining the growth of the fetus during gestation, and defects in its function result in fetal growth restriction or, if more severe, fetal death. Several molecular pathways have been identified that are essential for development of the placenta, and mouse mutants offer new insights into the cell biology of placental development and physiology of nutrient transport.

Development of structures and transport functions in the mouse placenta.

Modern evolutionary biology is founded on the Mendelian-genetic model of inheritance, but it is now clear that this model is incomplete. Empirical evidence shows that environment (encompassing all external influences on the genome) can impose transgenerational effects and generate heritable variation for a broad array of traits in animals, plants, and other organisms. Such effects can be mediated by the transmission of epigenetic, cytoplasmic, somatic, nutritional, environmental, and behavioral variation. Building on the work of many authors, we outline a general framework for conceptualizing nongenetic inheritance and its evolutionary implications. This framework shows that, by decoupling phenotypic change from the genotype, nongenetic inheritance can circumvent the limitations of genetic inheritance and thereby influence population dynamics and alter the fitness landscape. The weight of theory and empirical evidence indicates that nongenetic inheritance is a potent factor in evolution that can engender ...

/pdf/nongenetic-inheritance-and-its-evolutionary-implications-15vu8czjdx.pdf

Nongenetic Inheritance and Its Evolutionary Implications

Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth1,2,3,4. The insulin-like growth factor II gene (Igf2) is paternally expressed in the fetus and placenta5. Here we show that deletion from the Igf2 gene of a transcript (P0)6,7 specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. We show that passive permeability for nutrients of the mutant placenta is decreased, but that secondary active placental amino acid transport is initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. Our study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting8. We propose that the Igf2 gene, and perhaps other imprinted genes, control both the placental supply of, and the genetic demand for, maternal nutrients to the mammalian fetus.

Jennifer Hughes

Papers

Placental-specific IGF-II is a major modulator of placental and fetal growth